CFTR antisense phosphorothioate oligodeoxynucleotides (S-ODNs) induce tracheo-bronchial mucin (TBM) mRNA expression in human airway mucosa

Mucus hypersecretion is a critical component of cystic fibrosis (CF) pathog enesis. The effects of dysfunction of the cystic fibrosis transmembrane reg ulator (CFTR) on mucin expression were examined using the tracheo-bronchial mucin ( TBM) gene as an indicator. TBM mRNA expression was assessed in a h uman bronchial epithelial cell line (HBE1) and human nasal mucosal explants in vitro. Antisense phosphorothioate oligodeoxynucleotides (S-ODN) to TBM suppressed baseline expression of TBM mRNA in both systems, but had no effe ct on glyceraldehyde phosphate dehydrogenase mRNA (GAPDH) expression. Sense and missense (multiple scrambled control oligonucleotides) S-ODNs had no e ffect. 8Br-cAMP and PGE1 significantly elevated TBM mRNA expression. These increases were also specifically inhibited by the antisense S-ODNs. In orde r to induce a CF-like state, S-ODN to CFTR were added to explants. Antisens e CFTR S-ODNs were anticipated to reduce the expression of cellular CFTR pr otein, and the level of CFTR function. Antisense, but not sense or missense , CFTR S-ODN significantly increased TBM mRNA expression. These data sugges t that mucin hypersecretion in CF may be a direct consequence of CFTR dysfu nction; the specific mechanism through which this effect is mediated is not known.